Process for the preparation of 4-demethoxydaunomycinone, the aglycone of 4-demethoxy-daunorubicin

Abstract

4-Demethoxy-daunomycinone I: ##STR1## the known aglycone of 4-demethoxy-daunorubicin, is prepared by protecting the 13-keto group of 4-demethyl-daunomycinone, sulfonylating the 4-hydroxy group, reacting the sulfonylated compound with an amine, removing the amino protecting group from the resultant 4-demethyl-4-(protected amino)-13-dioxolanyl-daunomycinone, diazotizing the thus-freed 4-amino group and reducing under mild conditions the resulting diazonium compound.

We claim: 
     
       1. A process for the preparation of 4-demethoxydaunomycinone of formula (I): ##STR15## which process comprises: (a) protecting the 13-keto group of 4-demethyldaunomycinone of formula (2): ##STR16##  by treatment with ethylene glycol; (b) reacting the resultant 4-demethyl-13-dioxolanyldaunomycinone of formula (3): ##STR17##  with a sulfonyl chloride of formula II:   R--SO.sub.2 Cl                                             (II)      wherein R represents an alkyl group of from 1 to 10 carbon atoms optionally substituted by one or more halogen atoms or an aryl group optionally substituted by halogen, alkyl, alkoxy or nitro, in the presence of N,N-diisopropylethylamine and a catalytic amount of 4-dimethylamino-pyridine.   (c) reacting the resultant sulfonated 4-demethyl-13-dioxolanyl-daunomycinone of formula (4): ##STR18##  wherein R is as defined above, with an amine of formula III:   R.sup.1 (R.sup.2)CH--NH.sub.2                              (III)        wherein R 1  and R 2  each independently represents a hydrogen atom or a phenyl group bearing one or more alkoxy groups;   (d) removing the amino protecting group from the resultant 4-demethyl-4-(protected amino)-13-dioxolanyl-daunomycinone of formula (5): ##STR19##  wherein R 1  and R 2  are as defined above; (e) diazotising the 4-amino group of the resultant 4-demethoxy-4-amino-daunomycinone of formula (6): ##STR20## and (f) reducing the resultant diazo-derivative of formula (7): ##STR21##  under mild conditions, thereby to obtain 4-demethoxydaunomycinone of formula I.   
     
     
       2. A process according to claim 1, wherein the 4-demethyl-daunomycinone of formula (2) has been prepared by demethylation of daunomycinone of formula (1): ##STR22## 
     
     
       3. A process according to claim 2, wherein demethylation is effected by reflux with aluminium chloride in an inert organic solvent. 
     
     
       4. A process as claimed in claim 1, wherein step (a) is effected by treatment with ethylene glycol and p-toluenesulfonic acid in benzene at the reflux temperature. 
     
     
       5. A process as claimed in claim 1, wherein the sulfonyl chloride of formula (II) in step (b) is p-toluenesulfonyl chloride or 4-fluorophenylsulfonyl chloride. 
     
     
       6. A process as claimed in claim 1, wherein the amine of formula (III) in step (c) is 4-methoxybenzylamine or 3,4-dimethoxybenzylamine. 
     
     
       7. A process as claimed in claim 1, wherein step (d) is effected by reaction with trifluoroacetic acid. 
     
     
       8. A process as claimed in claim 1, wherein step (e) is effected using sodium nitrite. 
     
     
       9. A process as claimed in claim 1, wherein step (f) is effected using hypophosphorous acid. 
     
     
       10. A process for the preparation of 4-demethoxydaunomycinone of formula (I): ##STR23## comprising: (a) protecting the 13-keto group of 4-demethyldaunomycinone of formula (2): ##STR24##  by treatment with ethylene glycol and p-toluenesulfonic acid, in benzene at the reflux temperature, (b) reacting the resultant 4-demethyl-13-dioxolanyldaunomycinone of formula (3): ##STR25##  with an arenesulfonyl chloride selected from the group consisting of p-toluenesulfonyl chloride and 4-fluorophenylsulfonyl chloride, in the presence of N,N-diisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine,   (c) reacting the sulfonated 4-demethyl-13-dioxolanyldaunomycinone of formula (4): ##STR26##  wherein R is selected from the group consisting of p-tolyl and 4-fluorophenyl, with an amine selected from the group consisting of 4-methoxybenzylamine and 3,4-dimethoxybenzylamine,   (d) removing the amino protecting group from the resultant 4-demethy-4-(protected amino)-13-dioxolanyldaunomycinone of formula (5): ##STR27##  wherein R 1  is selected from the group consisting to 4-methoxyphenyl and 3,4-dimethoxyphenyl, by reaction with trifluoroacetic acid,   (e) diazotising the 4-amino group of the resultant 4-demethoxy-4-aminodaunomycinone of formula (6): ##STR28##  with sodium nitrite, and (f) reducing the resultant 4-diazoniumdaunomycinone of formula (7): ##STR29##  with hypophosphorous acid.   
     
     
       11. A process as claimed in claim 10, wherein said 4-demethyldaunomycinone of formula (2) is prepared by demethylation of daunomycinone of formula (1): ##STR30## effected by aluminum chloride in an inert organic solvent heated to reflux.